All these tests can be used to quantify LDH activity in a wide variety of samples including serum, tissue extracts, cell line lysates or cerebrospinal, peritoneal and pleural fluids [ 42 , 43 , 44 , 45 , 46 ].
They are also commonly used for monitoring the cytotoxicity and cell viability in cell cultures [ 47 ]. The fractionation of LDH isoforms can be performed by native electrophoresis on different media such as agarose gel, cellulose-acetate or polyacrylamide gel, ion exchange chromatography or affinity chromatography [ 18 , 19 , 22 , 23 , 24 , 27 , 31 , 48 ]. The LD5 fraction, known as the cathodic fraction, composed of four A subunits, is the slowest LDH isoform [ 20 , 22 , 23 , 27 , 31 ].
In extreme cases, next to the LD5 form, a very characteristic, additional band showing lactate dehydrogenase activity, has also been observed. Additionally, it was demonstrated that extracellular lactate, the end product of LDH activity, can be used for the assessment of human T cell proliferation and activation [ 52 ]. The widespread presence of LDH in cells, isoenzymatic tissue specificity and changes in the expression of individual subunits of this enzyme, associated with changes in tissue metabolic functions e.
However, more recent studies have shown that LDH is a non-specific diagnostic marker for cancers [ 23 , 54 , 58 ]. LDH activity determined in urine, although proposed as a marker of bladder or kidney neoplastic changes, was found to be elevated also in cases of upper urinary tract infections [ 85 ].
Similar difficulties arise when attempting to differentiate benign and malignant tumors based on total LDH activity [ 54 ]. However, in cases of blood or breast cancers, it is suggested to determine total LDH activity as a prognostic factor [ 9 , 61 ]. The value of total lactate dehydrogenase activity also seems to be a useful marker in making decisions about therapeutic management of testicular cancer patients [ 64 , 65 ]. Low LDH activity is associated with a high probability of complete remission of the disease and a good prognosis [ 9 , 23 , 54 ].
Increased total LDH activity is observed in most tumor tissues or even precancerous lesions, although this is not the rule [ 81 ]. Total LDH activity does not change significantly, e. It was suggested that the increase in LDH activity is influenced by the presence of necrotic processes within the tumor tissue [ 21 ].
On the other hand, it is known that cancerous tissues, in comparison with normal tissues, are characterized by the presence of a much larger number of connective tissue components, which, according to some authors, may be the cause of false low results [ 67 ]. Most human cancer tissues, in addition to increased total LDH activity [ 18 , 20 ], show changes in the ratio of lactate dehydrogenase isotypes, which tend to increase the expression of forms with the predominance of the A subunit [ 22 , 60 ].
Significant changes in favor of LDH-A isoenzymes have been observed in many malignancies, particularly those located in the thyroid, colon, uterus and ovaries, stomach, kidneys, central nervous system and lungs [ 9 , 19 , 20 , 21 , 22 , 54 , 66 , 67 , 68 , 72 , 80 , 84 ]. Less frequently, significant changes in the number of LDH-B isoforms are observed.
In the case of benign lesions, lactate production is much lower than in malignant tumors, and the percentage of individual isoforms does not differ significantly from that determined in normal tissues from which the lesions originate [ 68 , 72 ]. Although the mechanism regulating the expression of lactate dehydrogenase subunits and the synthesis of active tetramers is unknown, it is known that the ldha and ldhb genes are influenced by separate gene control regions [ 19 , 20 , 21 , 22 , 23 ].
The various genetic variants of the A and B subunits [ 23 , 84 ] observed in humans in no form known to date have been associated with neoplastic transformation, and although there was found an active LDH isoform LDHK with different structural and biochemical properties in human sarcomas, it was finally demonstrated that this enzyme, produced by cells infected with Kirsten virus, is fully encoded by the virus and used by it to control transcription [ 23 , 86 ].
Shim et al. The fact is that in the case of transformed cells, tyrosine phosphorylation of some proteins, including LDH, which do not function in such forms in normal cells, is observed [ 87 ]. Kawamoto found that LDH isozyme levels tended to increase in the order from LD1 to LD5 in both noninvasive and advanced breast cancers compared with normal breast tissues [ 60 ].
A number of studies have shown that there is a zone around the tumor in which, despite the lack of visible morphological changes, changes in the activity of LDH isoenzymes are observed [ 19 , 20 , 66 , 67 , 68 ].
These authors concluded that the reorientation of LDH isoenzymatic activity in histologically normal tissues surrounding the tumor must be due to an impaired metabolic balance reflecting precancerous changes. It may suggest that metabolic reprogramming in cancer cells precedes the morphological changes related to malignancy. However, it should be remembered that LDH isoenzyme patterns in tissues are always the resultant of the isoenzymograms of individual components of a given tissue [ 54 ].
Serum LDH, beyond its diagnostic and prognostic role, has also proved to be a useful indicator of the effectiveness and efficiency of anticancer therapy Table 1. Many clinical studies have supported the utility of LDH, among others, in the estimation of the likely course and outcome of multiple cancer types. Bar et al. LDH isoenzyme levels in the serum were tested in patients with colorectal cancers receiving chemotherapy along with the antiangiogenic drugs bevacizumab or cediranib, potent inhibitors of vascular endothelial growth factor receptor VEGFR tyrosine kinases.
Isoenzymes associated with a hypoxic metabolism turned out to be a negative prognostic marker. Moreover, it was observed that patients with higher expression of hypoxia-related LDH isoenzymes had a trend towards a better outcome from cediranib as compared to bevacizumab. To sum up, the study proved that progression-free survival and overall survival are related to the relative LDH isoenzymes levels, independently of the treatment.
In general, it also confirmed that both high levels of hypoxic LDH isoenzymes and high total LDH serum levels can be related to the poor prognosis [ 69 ]. Similar conclusions were reported by Anami et al.
They also observed that higher LDH levels correlated strongly with shorter survival of patients with small-cell lung cancer SCLC [ 73 ]. Because an elevated LDH level was found to be an unfavorable indicator for survival in cancer patients, it was suggested that lactate dehydrogenase can be used as a marker of tumor aggressiveness.
An analysis carried out by Cook et al. Furthermore, it was demonstrated that LDH levels highly correlate with survival in patients with bone metastases from breast cancer, and the significance of previously described prognostic factors was corroborated [ 91 ].
A study conducted by Inomata et al. It was also found that patients with higher plasma LDH levels had shorter progression-free survival and overall survival periods in comparison to patients with lower plasma LDH levels [ 74 ]. Yu et al. The conclusion was that levels of LDH were indeed associated with the systemic inflammatory response and served as a major prognostic predictor of overall survival.
Serum LDH levels were shown to predict overall survival in patients with advanced pancreatic cancer after gemcitabine-based palliative chemotherapy, and low serum LDH levels strongly correlated with longer overall survival [ 70 ]. Next, it was found that levels of LDH may have significant prognostic value for the response to chemotherapy and survival also in patients with advanced triple-negative breast cancer.
The study shows that abnormal baseline LDH levels corresponded to a notably shorter overall survival in comparison to the patients whose LDH baseline levels were normal. The most objective response rate after first-line chemotherapy has been reported in patients whose LDH levels decreased to normal after treatment [ 62 ].
Li et al. Previously, Sun et al. Moreover, Peliazzari et al. However, Oya et al. These findings might suggest that serum LDH levels are correlated with the immunotherapy effect. Both immune checkpoint inhibitors and the effectiveness of nivolumab likely depend on both tumor biomarkers and the patient status.
Nagamine et al. Additionally, another interesting discovery was reported by Bilir et al. It suggests that serum LDH levels could be used for fentanyl prescription by clinicians for cancer pain in addition to the pain assessment tools [ 91 ]. Unfortunately, too low specificity and sensitivity of these changes means that LDH cannot be recommended as a specific marker in cancer diagnosis. However, the available data do not exclude the possibility that the measurement of LDH could serve as a valuable auxiliary factor for monitoring the course of certain cancer diseases.
The metabolism of tumors in the body. J Gen Physiol. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Metabolic control of glucose degradation in yeast and tumor cells. Adv Biochem Eng Biotechnol. Molecular and cellular regulation of glucose transporter GLUT proteins in cancer.
J Cell Physiol. Lactate dehydrogenase a promotes the invasion and proliferation of pituitary adenoma. Sci Rep. A unique glucose-dependent apoptotic pathway induced by c-Myc. Regulation of gene expression by hypoxia: integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element. Clin Chim Acta. Semenza GL. HIF upstream and downstream of cancer metabolism. Curr Opin Genet Dev. Dang CV. Links between metabolism and cancer.
Genes Dev. Energy management by enhanced glycolysis in G1-phase in human colon cancer cells in vitro and in vivo. Mol Cancer Res. A history of research on yeasts 9: regulation of sugar metabolism.
Lactate dehydrogenase isoenzymes a comparison of pyruvate-to-lactate and lactate-to-pyruvate assays. Clin Chem. Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase. Structural characterization of the apo form and NADH binary complex of human lactate dehydrogenase. Acta Crystallogr D Biol Crystallogr. Active-loop dynamics within the Michaelis complex of lactate dehydrogenase from Bacillus stearothermophilus.
Two-dimensional gel electrophoresis of urinary proteins in kidney diseases. Contrib Nephrol. Wroblewski F, Gregory KF. Lactic dehydrogenase isozymes and their distribution in normal tissues and plasma and in disease states.
Ann N Y Acad Sci. Structural and functional properties of the H and M subunits of lactic dehydrogenases. Langvad E. Lactate dehydrogenase isoenzyme patterns in bronchogenic carcinoma. Eur J Cancer. Some characteristics of lactate dehydrogenase isoenzymes in tumours of the female genital tract. Usefulness of lactate dehydrogenase and its isoenzymes as indicators of lung damage or inflammation. Eur Respir J. Methods for the separation of lactate dehydrogenases and clinical significance of the enzyme.
J Chromatogr B Biomed Appl. PubMed Article Google Scholar. LDHC: the ultimate testis-specific gene. J Androl. Gupta GS. LDH-C4: a target with therapeutic potential for cancer and contraception. Mol Cell Biochem. Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer. Cancer Res. The objective of the study presented by Hoogmoed et al.
They found that the mean serum LDH activity in horses with nonseptic peritonitis was significantly higher than in horses with septic peritonitis and in healthy horses. Horses with septic peritonitis had higher LDH activities in peritoneal fluid than in serum. Horses with nonseptic peritonitis did not have significant differences in LDH activities between peritoneal fluid and serum.
The high mean serum LDH activity in horses with nonseptic and septic peritonitis may reflect absorption from the peritoneal fluid [ 91 ]. Peritoneal fluid LDH activity may be useful in the diagnosis of sepsis in the nonsurgical horse, but it does not appear to be a valuable diagnostic aid of the postsurgical horse because significant differences were not found in the peritoneal fluid LDH activities between the horses with septic and nonseptic peritonitis.
LDH activity in equine pleural and synovial fluid has been also used to detect sepsis with the potential advantages of speed, ease of measurement, and lower cost relative to bacterial cultures [ 92 , 93 ]. Allwin et al. Among the several parameters, LDH was found to be significantly elevated in elephants with moderate and severe colic.
This was in accordance with the report of Sabev and Kanakov [ 95 ] who reported extremely elevated LDH activity in elephants with caecal impaction. Sobiech and Kuleta [ 96 ] evaluated selected blood biochemistry parameters in calves during the course of diarrhoea. In sick calves, they observed insignificant, slightly higher total LDH activity and a significant increase in LDH 1 activity together with a decrease in LDH 5 isoenzyme activity. Similar results were obtained while investigating changes in the isoenzyme profile of LDH in the serum of diarrhoea-suffering goat kids [ 97 ].
Biochemical studies have shown that LDH isoenzymes are present in uterine secretions and that LDH activities vary with the stage of the estrous cycle [ 99 ]. Wright and Grammer [ ] evaluated serum LDH isoenzyme patterns in open and pregnant Holstein and Hereford cows as a method of detecting pregnancy.
LDH 4 and LDH 5 were found in higher concentration in pregnant versus open Holstein cows and no differences were found in serum LDH isoenzyme patterns between pregnant and open Hereford cows.
However, differences in concentration of all five LDH isoenzymes were observed between Holstein and Hereford cows. Peripartal serum LDH activity was measured in dairy cows in order to examine the association between retained fetal membranes RFM and enzyme activity [ ].
LDH activities in nonretained and retained placenta cows were similar. LDH data showed a moderate increase in activities starting from day 3 before parturition until day 3 postpartum in both groups of cows, but the difference was not significant. However, the differences in LDH activities on different days within nonretained and retained placenta cows were significant. Results indicate that prepartal changes in LDH activities are not predictive of placental retention postpartum.
These increased serum LDH activities during the peripartum period in both groups are in contrast to a study presented by Dutta and Dugwekar [ ]. In their study, higher prepartum serum activities of LDH were demonstrated in cows which subsequently retained fetal membranes after parturition. The results revealed that the levels of LDH were significantly higher in cows with RFM during late gestation and continued to be higher until 5th day postpartum.
Thus, it seems probable that prepartum increases in LDH activities could be useful indicator of the presence of uterine and placental pathology. The reason for the rise in peripartum LDH activities is open to speculation. It is noteworthy that LDH activity increased dramatically in the amniotic fluid just before bacterial induced fetal death and abortion, without comparable changes in LDH activity in the maternal plasma [ ].
This observation suggests that the fetoplacental tissues are a source of LDH. Analysis of total LDH activity and predominantly its isoenzyme pattern can significantly contribute to the diagnosis of diseases, which are linked to tissue damage.
Identification of isoenzymes that are causing the increase in total LDH activity could increase the diagnostic value of LDH activity. However, isoenzyme analysis requires special assays that are not routinely and widely available in each laboratory, and species variations in tissue distributions make interpretations difficult.
By itself, serum LDH activity is a screening test for some tissue damage and, in a group of tests, LDH activity provides additional information that may help explain activities of more tissue-specific enzymes.
Presented data points out that analysis of activity of LDH and its isoenzymes has clinical and diagnostic importance in laboratory diagnosis in animals. Knowing the physiological differences and specifics of each animal species forms the basis for their implementation and use in the veterinary clinical pathology.
Even though LDH and its isoenzymes examinations are not routinely used in veterinary laboratory diagnosis, many reports suggested their usefulness in the diagnostics of animal diseases. This work was supported by the Vega scientific grant nos.
This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.
Read the winning articles. Journal overview. Special Issues. Academic Editor: Sumanta Nandi. Received 17 Feb Accepted 21 May Published 15 Jun Introduction The use of biomarkers in medicine lies in their ability to detect disease and support diagnostic and therapeutic decisions.
Table 1. References A. Tzouvelekis, G. Kouliatsis, S. Anevlavis, and D. Beatty and D. Preus, B. Karsten, and A. Yasuda, K. Tateyama, B.
Syuto, and K. View at: Google Scholar D. Heinova and J. Heinova, J. Blahovec, and I. Rosival, Y. Avidar, and E. Lott and E. Lott, P. Wolf, and A. Sawhney, Eds. View at: Google Scholar K. Johnson-Davis and G. Bishop, E. Fody, and L. Schoeff, Eds. View at: Google Scholar H. Huijgen, G. Sanders, R.
Koster, J. Vreeken, and P. View at: Google Scholar J. View at: Google Scholar P. Sobiech, Z. Kuleta, and M. Messmer, and H. View at: Google Scholar A. View at: Google Scholar E. Bogin, G. Ziv, J. Avidar, B. Rivetz, S. Gordin, and A. Babaei, L. Mansouri-Najand, M. Molaei, A. Kheradmand, and M. Davies, D. Long, A. McCarthy, and M. Weiss, M. Bauer, L. Whiteley, S. Maheswaran, and T.
Reinhold, G. Kreutzer, A. Gerischer, and R. Yasuda, B. Syuoto, K. Too, and S. View at: Google Scholar R. Dawra, O. Sharma, L. Krishna, and J. Sobiech and Z. Enemark, R. Drastich, V. Kummer, and J. Tanaka, S. Urabe, A. Takeguchi et al. Mori, P. Kenyon, N. Stockham and M. Allen, P. Steele, H. Masters, and M. Osame, H. Takahashi, H. Furuoka, T. Matsui, and S. View at: Google Scholar M. Nevole, L. Malota, and B.
Thrall, G. Weiser, R. Allison, and T. Viguier, S. Arora, N. Gilmartin, K. Welbeck, and R. Zank and B. Bogin and G. View at: Google Scholar S. Hiss, U. Mueller, A. Neu-Zahren, and H. View at: Google Scholar F. Yang, X. Li, B. He et al. Chagunda, T. Larsen, M.
Bjerring, and K. Vyavahare, S. Bonde, N. Mangle, V. Ballamwar, and S. View at: Google Scholar B. Kato, K. Mori, and N. Nizamlioglu and O. Atroshi, J. Parantainen, S. Sankari, M. After the procedure, the elastic band is removed. Once the blood has been collected, the needle is removed and the area is covered with cotton or a bandage to stop the bleeding.
Collecting the blood for the test will only take a few minutes. Either method heel or vein withdrawal of collecting a sample of blood is only temporarily uncomfortable and can feel like a quick pinprick.
Afterward, there may be some mild bruising, which should go away in a day or so. The blood sample will be processed by a machine. The results are commonly available within a day or two. The LDH test is considered a safe procedure. However, as with many medical tests, some problems can occur with having blood drawn, like:. Having a blood test is relatively painless. Still, many children are afraid of needles. Explaining the test in terms your child can understand might help ease some of the fear.
Allow your child to ask the technician any questions he or she might have.
0コメント